New mutation of the TP53 gene associated with the hereditary breast cancer in a young Tuvinian woman

Background. The identification of the ethnospecific mutations associated with hereditary breast cancer remains challenging. Next generation sequencing (Ngs) technology fully enables the compilation of germline variants associated with the risk for inherited diseases. Despite the success of the Ngs, up to 20 % of molecular tests report genetic variant of unknown significance (Vus) or novel variants that have never been previously described and their clinical significances are unknown. To obtain extended information about the variants of the unknown significance, it is necessary to use an alternative approach for the analysis of the Ngs data. To obtain extended characteristic about the unknown significance variants, it is necessary to search for additional tools for the analysis of the Ngs data. Material and methods. We reclassified the mutation of the unknown significance using the activedrivedb database that assessed the effect of mutations on sites of post-translational modifications, and the proteinpaint tool that complemented the existing cancer genome portals and provided a comprehensive and intuitive view of cancer genomic data. Results. In this study, we report a 44-year-old tuvinian woman with a family history of breast cancer. Based on the Ngs data, mutational analysis revealed the presence of the lrg_321t1: c.80c>t heterozygous variant in exon 2, which led to the proline to leucine change at codon 27 of the protein. In the dbpubmed database, this mutation was determined as unknown significance due to data limitation. According to the data of the activedriverdb tool, this mutation is located distally at the site of post-translational protein modification, which is responsible for binding to kinases that regulate genes of the cell cycle, etc. (atm, chek2, cdk, mapk). In accordance with proteinpaint tool, the lrg_321t1: c.80c>t mutation is located in functionally specialized transactivation domains and codon of the tp53 gene, where the pathogenic mutation associated with li-Fraumeni syndrome has been earlier described. Conclusion. This report is the first to describe a new variant in the tp53 gene (rs1555526933), which is likely to be associated with hereditary cancer-predisposing syndrome, including li-Fraumeni syndrome, in a tuvinian Bc patient with young-onset and familial Bc.

Segmental neurofibromatosis with compression of the spinal cord at the cervical level. Literature review and case report

Background. Neurofibromatosis is a fairly rare disease (1/3000). In 1992, V. Riccardi described seven types of neurofibromatosis. Segmental neurofibromatosis (sh), also known as type V neurofibromatosis, is an extremely rare variant characterized by the development of typical cutaneous manifestations or one body segment neurofibromas. Clinical case. Currently, the literature describes about 100 cases of sh and only one of them with compression of the spinal cord. We present our first case of this nosological form with spinal cord compression in a Russian patient. A 70-year-old patient, due to an increasing paresis in the left extremities, underwent mri of the cervical spine, which revealed solid tumors located extramedullary intra-extradurally at the level of c2-c3 vertebrae with pronounced compression of the spinal cord. At the time of hospitalization, clinical presentation was characterized by deep spastic tetraparesis (1–2 points), impairment of all types of sensitivity from the c4 level by the conductive type, and dysfunction of the pelvic organs by the type of delay. Karnofsky index was 50 %, 2 points on the Fim scale. Standard c2-c3 vertebrae laminectomy was performed. Spinal cord compression was eliminated due to the removal of intradural tumors. Subsequently, extradural tumors were removed step by step. On histological examination, tumors were represented by intertwining bundles of elongated schwann cells with wavy nuclei with pointed ends and ileogenic fibers. Mucin present in the stroma separated cells and fibers. Conclusion. Sn is a rare type of neurofibromatosis. However, from the point of view of genetics, it is most likely incorrect to attribute it to a separate type of neurofibromatosis, since the cause of its development is mosaicism of somatic cells due to mutation of the NF 1 gene. Sn is rarely manifested by the development of spinal nerves multiple neurofibromas, however, it can be accompanied by a gross neurological deficit caused by compression of the spinal cord such neurofibromas. Surgical treatment is based on basic and special surgical principles that determine the anatomical and morphological characteristics of the area of intervention, the compliance of which allows for good treatment results.

Sructural rearrangements of NTRK genes: characteristics, methods of detection and targeted therapy for cancer

Background. The first-generation trk inhibitors, larotrectinib and entrectinib, were approved by the u.s. Food and drug administration (Fda) for the treatment of advanced solid tumors harboring NTRK gene fusions in November 2018 and in august 2019, respectively. The purpose of the study was to present upto-date data on the structure and functions of ntrk genes, the frequency of occurrence of rearrangements with their participation, the consequences of their occurrence at the cellular level, methods of detecting such rearrangements, as well as targeted drugs used in the presence of chimeric NTRK genes. Material and methods. A systemic literature search was conducted in pubmed ncbi, Web of science, scopus databases. Results. The products of NTRK genes are receptors for neurotrophins, and their high expression is normally observed only in a narrow range of tissue types. Intrachromosomal or interchromosomal rearrangements lead to a significant increase in the level of expression of the chimeric gene regulated by the strong promoter of the partner gene. The high transcriptional activity of such a gene, along with the constant activation of the kinase activity of the protein product, leads to the activation of metabolic pathways responsible for cell escape from apoptosis and disruption of the regulation of the cell cycle. The occurrence of chimeric NTRK genes varies between different types of tumors, with the highest (up to 90 %) in rare cancers (secretory carcinoma of the breast, secretory carcinoma of the salivary glands, congenital mesoblastic nephroma, children’s fibrosarcoma). Larotrectinib and entrectinib are highly effective targeted drugs in suppressing the growth of a tumor carrying NTRK rearrangements, regardless of the type of tumor. In this regard, the introduction of new high-precision methods for the detection of chimeric NTRK genes, as well as the study of the mechanisms of the development of resistance with the assumption of ways to overcome it, seems relevant. Conclusion. Rearrangements of NTRK genes are quite common in various types of oncology and are an effective target for modern targeted drugs.

On the role of autophagy in the progression of differentiated thyroid cancer (literature review)

The aim of the study was to analyze and summarize available literature data on the role of autophagy in thyroid cancer. Material and methods. We analyzed 34 publications available from pubmed and elibrary. Ru databases concerning thyroid cancer and autophagy. Results. The review discussed the role of autophagy in the progression of thyroid cancer. The development of autophagy-targeted therapy was shown can improve treatment for thyroid cancer. Differentiated thyroid cancer (dtc) is the most common endocrine malignancy. Treatment of dtc patients who are resistant to radioactive iodine therapy is a major challenge. Molecular targeted therapy using tyrosine kinase inhibitors significantly improves treatment outcomes. Conclusion. To enhance the therapeutic effect of treatment with multi-target tyrosine kinase inhibitors, as well as to overcome drug resistance, it is necessary to study the role of autophagy in the development and progression of thyroid cancer.

Clinical case of successful treatment of COVID-19 infection manifested with B-cell acute lymphoblastic leukemia

The novel corona virus disease 2019 (covid-19) is currently a global threat. Cancer patients constitute a group that is at high risk of covid-19 infection with a more severe disease course and higher mortality rate. Case description. We report a case of covid-19 occurring concurrently with B-cell acute lymphoblastic leukemia (all) in a young male patient. After verification of the morphological and immunophenotypic profiles of leukemia, the patient receivedall treatment (all-2009 protocol) with concurrent administration of antiviral and antibacterial drugs, as well as immunoglobin replacement therapy. Neutropenia caused by cytostatic treatment led to the progression of lung damage and respiratory failure, which required the withdrawal of cytostatic drugs. The patient was transferred to the intensive care department, where dexamethasone therapy as well as antibacterial and antifungal therapy was continued. Since the lung damage reached 75 % and respiratory failure began to increase, non-invasive ventilation of the lungs was started. Clinical and hematological remission with hematologic recovery and subsequent pneumonia regression was achieved. However, long-term persistence of the virus was observed, and therefore the strategy for treating acute lymphoblastic leukemia was revised. Maintenance therapy with mercaptopurine and methotrexate was administered. After elimination of the virus on the 56th day from the initial positive test, therapy according to the all-2009 protocol was continued. Conclusion. The tactics of treating cancer patients with hemoblastosis during a pandemic should be selected individually with an assessment of the potential benefits and risk of life-threatening complications.

Humanized animals as models of experimental oncology (review)

The humanization of immunodeficient animals allows us to study the growth of xenografts of human malignant tumors and their response to therapeutic effects, taking into account processes in the immune system and tumor zone, which have a significant impact on oncogenesis and the effectiveness of antitumor therapy. Such experimental models are currently considered as the most advanced tool in the development of personalized antitumor treatment. The lines of immunodeficient animals most commonly used for the transplantation of mature and stem human immune cells have been characterized. The main sources of human immune cells when implementing the hu-pbl and hu-cd34+ models, as well as the blt model (as an option to the cd34+ model) are described. The basic procedures necessary for reproducing each model, their modification in adult and newborn animals are outlined as well as the parameters of immunosuppressive radiation exposure, preceding the transplantation of human hematopoietic stem cells. The main results of the humanization of immunodeficient animals and examples of the use of these models for the purposes of fundamental and clinical oncology are described. The main problems of this direction are discussed. The review is based on an analysis of the literature presented in the scopus, web of science, medline, risc and others databases over the past 7 years (over 80 % of literature sources, with more than over 50 % of studies published over the last 3 years).

Evaluation of the antitumour activity of local intraperitoneal hyperthermia in a model of advanced high-grade ovarian carcinoma in rats

In our study we carried out an exploratory assessment of the antitumor activity of hyperthermic intraperitoneal perfusion (Hipep) with 0.9 % sodium chloride solution and compared it with the effect of a single normothermic intraperitoneal (i.p.) Administration of cisplatin in the maximum tolerated dose (mtd). Thirty-six mature female Wistar rats with transplanted i.p. Syngeneic ovarian carcinoma were randomized into three groups: control group (2 ml of 0.9 % sodium chloride i.p. At room temperature, n=12); cisplatin group (cisplatin 4 mg/kg i.p. At room temperature, n=12); Hipep group (open i.p. Perfusion with 0.9 % sodium chloride solution at a temperature of 40,5–41,5 °c for 45 minutes, n=12). The primary endpoint was the overall survival (os) of the animals in each of the three groups. The total peritoneal cancer index (pci), weight and degree of ascites haemorrhagia were assessed at autopsy. The median os in the control group, Hipep, and cisplatin was 19, 39, and 40 days, respectively (log-rank test р<0.0001). In comparison to the control group, the differences were statistically significant for both cisplatin (HR=0.22; 95 % ci: 0.08–0.62; log-rank test р<0.0001) and Hipep (HR=0.32; 95 % ci 0.13–0.82; log-rank test р=0.0013). There were no differences in os between the cisplatin and Hipep groups (log-rank test р=0.4853). The Hipep procedure was associated with a significant decrease in total pci, a tendency towards a decrease in the ascites weight and a higher severity of haemorrhagia. In terms of os, local hyperthermia, provided by Hipep without a cytostatic drug, was comparable with single normothermic i.p. Administration of cisplatin in mtd and exceeded the effects of the latter in relation to the development of peritoneal carcinomatosis.

Gastric cancer: modern approaches and prospects of treatment for peritoneal carcinomatosis (literature review)

Gastric cancer (gc) is one of the most common cancers worldwide. The majority of newly diagnosed gastric cancer cases present with distant metastases. Peritoneal carcinomatosis (pc) is the most unfavorable type of progression of primary gc, which occurs in 14–43 % of patients. The purpose of the study was to highlight modern approaches to the treatment of gc with pc. Material and methods. We analyzed 136 publications available from pubmed, medline, cochrane library, and elibrary databases. The final analysis included 46 studies that met the specified parameters. Results. The modern approaches to the treatment of gc with peritoneal carcinomatosis were reviewed, namely: cytoreductive surgery (crs), combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (crs/hipec); neoadjuvant intraperitoneal/systemic chemotherapy (nips) and pressurized intraperitoneal aerosol chemotherapy (pipac). The results of large randomized trials and meta-analyses were analyzed. Benefits and limitations of these trials were assessed. Conclusion. The peritoneal cancer index (pci) and the level of cytoreduction are two key prognostic factors for increasing the median overall survival. By reducing tumor volume through cytoreductive surgery, it is possible to allow tumor cells to re-enter the proliferative phase of the cell cycle and make them more sensitive to antitumor agents. The hematoperitoneal barrier is the main reason that prevents the effective delivery of drugs from the systemic bloodstream to the abdominal cavity, which is why the effect of systemic chemotherapy on peritoneal metastases is extremely limited. Intraperitoneal chemotherapy offers a more effective and intensive regional therapy, creating a so-called «depot» of a chemotherapy drug, thereby prolonging the effect of the administered drugs. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (crs + hipec) using the combination of surgical resection, cytotoxic chemotherapy, hyperthermic ablation of the tumor and hydrodynamic flushing, is a promising approach in the treatment of gc with peritoneal carcinomatosis.

Microsurgical reconstruction of the skull base and midface after orbitomaxillary resections for malignant tumors

Background. Orbitomaxillary resection includes exenteration of the orbital contents with resection of the inferior orbital and medial walls. The main goals are: reconstruction of soft tissue and bone structure defects, tamponade of the orbital cavity and/or its preparation for further ocular prosthetics, and reconstruction of the skull base defect. The purpose of the study to present the immediate results of orbitomaxillary resections in patients with malignant neoplasms of the skull base and midface. Material and methods. Between 2014 and 2020, 6 patients who previously underwent surgery for primary cancer (n=3) and recurrent cancer (n=3) were treated at the Head and Neck cancer department of N.N. Blokhin National medical Research center of oncology. To reconstruct defects after resection of bone structures (maxilla, frontal and nasal bones) and skin, a musculocutaneous alt-flap was used in 3 (50 %) cases and a fascial skin radial flap in 3 (50 %) cases. Results. The aesthetic result was assessed in 6 patients. In all cases, a satisfactory result was obtained. None of the patients who underwent resection of the dura mater followed by reconstruction had no symptoms of liquorrhea in the postoperative period. Conclusion. Flap selection depends on the defect size. In cases with a small defect size (up to 70 cm3), reconstruction with the radial fascial skin flap can be performed. If the defect size is more than 71 cm3, reconstruction with musculocutaneous alt flap can be the method of choice.

Heart failure in cancer patients

The purpose of the study was to conduct a systematic review of data on the role of heart failure (HF) in the development of cancer, as well as to discuss problems dealing with diagnosis and treatment of heart failure in cancer patients. Material and methods. A literature search was conducted using the Cochrane library, elibrary, medline, and embase databases over the past 7 years. The general mechanisms of heart failure and cancer, cardiotoxicity risk factors, and some aspects of the diagnosis and treatment of HF in cancer patients were analyzed. Results. The literature analysis indicates that cardiovascular disease and cancer have common risk factors. Several common pathophysiological mechanisms that associate HF with cancer have been identified. They include inflammation, oxidative stress, and neurohomonal activation. HF is known to be a common complication of aggressive cardiotoxic cancer therapy that can aggravate or trigger existing HF. Recent epidemiological studies have shown that the development of cancer is more common among patients with pre-existing HF. Although the reason for this relationship has not yet been identified, it is assumed that HF may be a pro-oncogenic condition. There are several strategies to prevent and treat toxicity of various chemotherapeutic drugs. They are all based on accurate patient selection, short- and longterm follow-up, and therapies that can prevent and delay cardiac dysfunction. Conclusion. The main goal of cardio-oncology is to prevent and treat of cardiotoxic effects of chemotherapy drugs. In this context, elucidation of the underlying mechanisms plays an important role in the development of strategies for the prevention of chemotherapy-associated cardiomyopathy. It is necessary to pay attention to the fact that there is more and more evidence that patients with HF have high risks of developing cancer, thereby requiring more attention. In general, understanding the direct and indirect mechanisms of the relationship between HF and cancer can help in the prevention and early diagnosis of these diseases.